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a "surfing" analogy a "surfing" analogy – surfer riding near the crest of wave – target concentration that produce considerable drug effects and recover quickly drug administration is terminated – large reduction in effects with small decrease in concentration

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the pharmacodynamic approach the pharmacodynamic approach – feedback mechanism(propofol titration to EEG and muscle relaxant) the pharmacokinetic approach the pharmacokinetic approach – TCI the pharmaceutical approach the pharmaceutical approach – unnecessary to hit the target with as much precisions and accuracy as with the other approaches Three approaches

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Pharmacokinetic considerations pharmacologic modeling pharmacologic modeling – fitting mathematical equations to raw pharmacologic data – a set of parameters that describe in quantitative terms a drug's disposition and effect in the body – pharmacokinetic parameters : clearance, distribution volumes, half life – " what the body does to the drug" – pharmacodynamic parameters : potency – " what the drug does to the body"

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The goal of PK-PD modeling The goal of PK-PD modeling – provide the practitioner with the knowledge necessary to formulate rational dosing scheme – accurately predicting the time course and magnitude of drug effect in any type of patients – to move dose-response analysis

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pharmacokinetic component : relationship between the drug dose and the time course of drug concentrations in the body pharmacokinetic component : relationship between the drug dose and the time course of drug concentrations in the body pharmacodynamic component : relationship between the drug concentration in the site of action and the drug effect pharmacodynamic component : relationship between the drug concentration in the site of action and the drug effect prediction regarding latency to peak effect, magnitude of effect, duration of effect prediction regarding latency to peak effect, magnitude of effect, duration of effect

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Pharmacodynamic considerations importance of pharmacodynamic drug interactions and synergy importance of pharmacodynamic drug interactions and synergy – pharmacodynamic drug interaction : frequently produced by design – modern day anesthesia : at least a two-drug process consisting of an analgesic and a hypnotic agent – anesthesiology is the practice of pharmacologic synergism using CNS depressants

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revolutionary advance in our understanding of IV anesthetic clinical behavior revolutionary advance in our understanding of IV anesthetic clinical behavior propofol : 3.5ug/ml as loss of consciousness in 50% pts 10-15ug/ml to supress to surgical stimuli 1ug/ml in the presence of opioid adjuvant propofol : 3.5ug/ml as loss of consciousness in 50% pts 10-15ug/ml to supress to surgical stimuli 1ug/ml in the presence of opioid adjuvant by using propofol-opioid ratio : applicable to any anesthetic case by using propofol-opioid ratio : applicable to any anesthetic case function of opioid pharmacokinetics : play a large part of selection of ratio function of opioid pharmacokinetics : play a large part of selection of ratio long acting fentanyl congeners : low opioid and high propofol long acting fentanyl congeners : low opioid and high propofol short acting opioid : low propofol short acting opioid : low propofol

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play in selecting the appropriate propofol- opioid ratio play in selecting the appropriate propofol- opioid ratio – hemodynamically compromised pt VS pt prone to nausea and vomiting isobologram is only a single "slice" through a much larger drug ineraction "surface" isobologram is only a single "slice" through a much larger drug ineraction "surface" response surface : tool to visualize the nature of the synergy of two drug class response surface : tool to visualize the nature of the synergy of two drug class

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– can be titrated up and down as necessary to meet the dynamic needs of the patient during rapid changing conditions of anesthesia and surgery – when rapid recovery is desirable – when the anesthetic requirement rapidly fluctuates – when opioid titration is unpredictable or difficult – when there is a substantial danger to opioid overdose – when "high-dose" opioid technique is advantageous but not going to be mechanically ventilated

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importance of formulation : propofol as an example importance of formulation : propofol as an example – the formulation of a drug can have an important influence on the drug's clinical behavior – propofol : lipid emulsion formulation pain on injection serious allergic reactions inadvertent contamination – prodrug non-lipid excipient lipid-based emulsion – may alter pharmacokinetic and pharmacodynamic characteristic

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computer-controlled infusion pump computer-controlled infusion pump – by coding a pharmacokinetic model into a computer program and linking it into an electric pump – design target concentration and calculate the necessary infusion rate by TCI system – gradually decrease the rate of infusion based on the pharmacokinetics – change the infusion rate frequently – require knowledge of the therapeutic concentration for clinical application